Trial Summary:

Inhibition of PARP is the best-established therapeutic approach exploiting defects in tumour homologous recombination (HR) DNA repair. Olaparib has shown anti-tumor activity in ovarian, breast and other solid tumor types with deleterious mutations in BRCA1/2. Tumors with compromised DNA repair due to defects in HR genes other than BRCA1/2 (eg ATM, RAD51C, RAD51D, PALB2, BAP1) may also be sensitive to PARP inhibition. DNA-damage and the resultant cell death and antigen release caused by PARP inhibition may increase the antigenicity of tumours with HD defects. As the tumour mutational landscape is a critical determinant of sensitivity to immune checkpoint blockade, patients with HR defects treated with a PARP inhibitor may benefit from drugs that block the PD-1/PD-L1 pathway. Inhibition of PD-L1 with durvalumab has shown durable anti-tumour effects.

We hypothesize that olaparib activity will extend to:

(i) cancers with somatic and germline BRCA1/2 mutations other than ovarian, breast and prostate cancer and

(ii) BRCA1/2 wild-type (wt) tumours with defects in other HR genes.

Furthermore, we hypothesise that these tumours with HR defects treated with a PARP inhibitor are responsive to PD-L1 blockade and the combination of olaparib with durvalumab will have additive anti- tumour activity.

The aim of MoST substudies 6-8 is to assess the clinical activity of olaparib plus durvalumab in patients with advanced cancer and tumours with germline or somatic defects in HR DNA repair, including:

(i) Non-breast, ovarian or prostate cancers with mutations and deletions in BRCA1/2 genes;

(ii) Tumours with mutations and deletions in selected non-BRCA1/2 HR pathway genes, subgrouped post-hoc on the basis of their HR deficiency (HRD) score.

To be eligible for this substudy, participants must continue to meet all of the inclusion criteria and none of the exclusion criteria specified in the MoST framework protocol (sections 5.3-5.8) and, in addition, meet all the inclusion criteria and none of the exclusion criteria at the time of registration.

Supported By:

OHMR, CGMP, Astra Zeneca

Eligibility:

Patients with pathologically confirmed advanced or metastatic solid cancer of any histologic type with a focus on rare or neglected cancers. Patients will be enrolled in the MoST program for molecular screening and eligible for this study if a germline or somatic defect in HR DNA repair is found. Eligible genetic alterations include germline and somatic deleterious mutations and deletions in BRCA1/2 (excluding patients with breast, ovarian and prostate cancer) and in non-BRCA1/2 HR pathway genes including ATM, PALB2, RAD51C, RAD51D, CHEK1, CHEK2, ATR, CDK12, BAP1, BARD1, BRIP1 and FANC genes.

Registration ID:

ACTRN12617001000392

Participation:

National

Status:

Activation Date:

17/11/2017

Chairs:

Anthony Joshua

Contact:

most.study@sydney.edu.au